Prostaglandin E receptor agonists for treatment of dry eye

ABSTRACT

The present invention relates to use of prostaglandin E receptor agonists and partial agonists to stimulate mucin secretion to treat dry eye, keratoconjunctivitis, Sjogren&#39;s syndrome and related ocular surface diseases.

This application is a 371 of PCT/US99/29733 filed on Dec. 14, 1999,which claims the benefits of provisional application No. 60/113,574filed Dec. 24, 1998.

FIELD OF THE INVENTION

The present invention relates to the use of prostaglandin E receptoragonists and partial agonists to stimulate mucin secretion to treat dryeye, keratoconjunctivitis, Sjogren's syndrome and related ocular surfacediseases.

BACKGROUND OF THE INVENTION

Dry eye is a common ocular surface disease afflicting millions of peoplein the U.S. each year, especially the elderly (Schein et. al.,Prevalence of dry eye among the elderly. American J. Ophthalmology,124:723-738, (1997)). Dry eye may afflict an individual with varyingseverity. In mild cases, a patient may experience burning, a feeling ofdryness, and persistent irritation such as is often caused by smallbodies lodging between the eye lid and the eye surface. In severe cases,vision may be substantially impaired. Other diseases, such as Sjogren'sdisease and cicatricial pemphigoid manifest dry eye complications.

Although it appears that dry eye may result from a number of unrelatedpathogenic causes, the common end result is the breakdown of the tearfilm, which results in dehydration of the exposed outer surface of theeye. (Lemp, Report of the Nation Eye Institute/Industry Workshop onClinical Trials in Dry Eyes, The CLAO Journal, 21(4):221-231 (1995)).Four events have been identified which singly or in combination arebelieved to result in the dry eye condition: a) decreased tearproduction or increased tear evaporation; b) decreased conjunctivalgoblet-cell density; c) increased corneal desquamation; and d)destabilization of the cornea-tear interface (Gilbard, Dry eye:pharmacological approaches, effects, and progress. The CLAO Journal,22:141-145 (1996)). Another major problem is the decreased mucinproduction by the conjunctival cells and/or corneal epithelial cells ofmucin, which protects and lubricates the ocular surface (Gipson andInatomi, Mucin genes expressed by ocular surface epithelium Progress inRetinal and Eye Research, 16:81-98 (1997)).

Practitioners have taken several approaches to the treatment of dry eye.One common approach has been to supplement and stabilize the ocular tearfilm using so-called artificial tears instilled throughout the day.Another approach has been the use of ocular inserts that provide a tearsubstitute or to stimulate endogenous tear production.

Examples of the tear substitution approach include the use of buffered,isotonic saline solutions, aqueous solutions containing water solublepolymers that render the solutions more viscous and thus less easilyshed by the eye. Tear reconstitution is also attempted by providing oneor more components of the tear film such as phospholipids and oils.Examples of these treatment approaches are disclosed in U.S. Pat. No.4,131,651 (Shah et. al.), U.S. Pat. No. 4,370,325 (Packman), U.S. Pat.No. 4,409,205 (Shively), U.S. Pat. No. 4,744,980 and U.S. Pat. No.4,883,658 (Holly), U.S. Pat. No. 4,914,088 (Glonek), U.S. Pat. No.5,075,104 (Gressel et. al.) and U.S. Pat. No. 5,294,607 (Glonek et.al.).

United States Patents directed to the use of ocular inserts in thetreatment of dry eye include U.S. Pat. No. 3,991,759 (Urquhart). Othersemi-solid therapy has included the administration of carrageenans (U.S.Pat. No. 5,403,841, Lang) which gel upon contact with naturallyoccurring tear film.

Another recent approach involves the provision of lubricating substancesin lieu of artificial tears. U.S. Pat. No. 4,818,537 (Guo) discloses theuse of a lubricating, liposome-based composition.

Aside from the above efforts, which are directed primarily to thealleviation of symptoms associated with dry eye, methods andcompositions directed to treatment of the dry eye condition have alsobeen pursued. For example, U.S. Pat. No. 5,041,434 (Lubkin) disclosesthe use of sex steroids, such as conjugated estrogens, to treat dry eyecondition in post-menopausal women; U.S. Pat. No. 5,290,572 (MacKeen)discloses the use of finely divided calcium ion compositions tostimulate tear film; and U.S. Pat. No. 4,966,773 (Gressel et. al.)discloses the use of microfine particles of one or more retinoids forocular tissue normalization.

Although these approaches have met with some success, problems in thetreatment of dry eye nevertheless remain. The use of tear substitutes,while temporarily effective, generally requires repeated applicationover the course of a patient's waking hours. It is not uncommon for apatient to have to apply artificial tear solution ten to twenty timesover the course of the day. Such an undertaking is not only cumbersomeand time consuming, but is also potentially very expensive.

The use of ocular inserts is also problematic. Aside from cost, they areoften unwieldy and uncomfortable. Further, as foreign bodies introducedin the eye, they can be a source of contamination leading to infections.In situations where the insert does not itself produce and deliver atear film, artificial tears must still be delivered on a regular andfrequent basis.

In view of the foregoing, there is a clear need for an effectivetreatment for dry eye that is capable of alleviating symptoms, as wellas treating the underlying physical and physiological deficiencies ofdry eye, and that is both convenient and inexpensive to administer.

Mucins are proteins which are heavily glycosylated withglucosamine-based moieties. Mucins provide protective and lubricatingeffects to epithelial cells, especially those of mucosal membranes.Mucins have been shown to be secreted by vesicles and discharged on thesurface of the conjuctival epithelium of human eyes (Greiner et. al.,Mucus Secretory Vesicles in Conjunctival Epithelial Cells of Wearers ofContact Lenses, Archives of Ophthalmology, 98:1843-1846 (1980); andDilly et. al., Surface Changes in the Anaesthetic Conjunctiva in Man,with Special Reference to the Production of Mucus from a Non-Goblet-CellSource, British Journal of Ophthalmology, 65:833-842 (1981)). A numberof human-derived mucins which reside in the apical and subapical cornealepithelium have been discovered and cloned (Watanabe et. al., HumanCorneal and Conjuctival Epithelia Produce a Mucin-Like Glycoprotein forthe Apical Surface, Investigative Ophthalmology and Visual Science(IOVS), 36(2):337-344 (1995)). Recently, a new mucin was reported to besecreted via the cornea apical and subapical cells as well as theconjunctival epithelium of the human eye (Watanabe et. al., IOVS,36(2):337-344 (1995)). These mucins provide lubrication, andadditionally attract and hold moisture and sebacious material forlubrication and the corneal refraction of light.

Mucins are also produced and secreted in other parts of the bodyincluding lung airway passages, and more specifically from goblet cellsinterspersed among tracheal/bronchial epithelial cells. Certainarachidonic acid metabolites have been shown to stimulate mucinproduction in these cells. Yanni reported the increased secretion ofmucosal glycoproteins in rat lung by hydroxyeicosatetraenoic acid(“HETE”) derivatives (Yanni et. al., Effect of IntravenouslyAdministered Lipoxygenase Metabolites on Rat Trachael Mucous Gel LayerThickness, International Archives of Allergy And Applied Immunology,90:307-309 (1989)).

The conventional treatment for dry eye, as discussed above, includesadministration of artificial tears to the eye several times a day. Otheragents claimed for increasing ocular mucin and/or tear productioninclude vasoactive intestinal polypeptide (Dartt et. al., Vasoactiveintestinal peptide-stimulated glycocongjugate secretion fromconjunctival goblet cells. Experimental Eve Research, 63:27-34, (1996)),gefarnate (Nakmura et. al., Gefarnate stimulates secretion of mucin-likeglycoproteins by corneal epithelium in vitro and protects cornealepithelium from dessication in vivo, Experimental Eye Research,65:569-574 (1997)), and the use of liposomes (U.S. Pat. No. 4,818,537),androgens (U.S. Pat. No. 5,620,921), melanocycte stimulating hormones(U.S. Pat. No. 4,868,154), phosphodiesterase inhibitors (U.S. Pat. No.4,753,945), retinoids (U.S. Pat. No. 5,455,265) andhydroxyeicosatetraenoic acid derivatives (U.S. Pat. No. 5,696,166).However, many of these compounds or treatments suffer from a lack ofspecificity, efficacy and potency and none of these agents have beenmarketed so far as therapeutically useful products to treat dry eye andrelated ocular surface diseases. Thus, there remains a need for anefficacious therapy for the treatment of dry eye and related diseases.

Prostaglandins are metabolite derivatives of arachidonic acid.Arachidonic acid in the body is converted to prostaglandin G₂, which issubsequently converted to prostaglandin H₂. Other naturally occurringprostaglandins are derivatives of prostaglandin H₂. A number ofdifferent types of prostaglandins are known in the art including A, B,C, D, E, F, G, I and J-Series prostaglandins (U.S. Pat. No. 5,151,444;EP 0 561 073 A1; Coleman et. al., VIII International Union ofPharmacology classification of prostanoid receptors: Properties,distribution, and structure of the receptors and their subtypes,Pharmacological Reviews, 45:205-229 (1994)). Depending on the number ofdouble-bonds in the α-(top chain) and/or the ω-chain (bottom chain), theprostaglandins are further classified with subscripts such as PGD₂,PGE₁, PGE₂, PGF_(2α), etc. (U.S. Pat. No. 5,151,444; Coleman et. al.,VIII International Union of Pharmacology classification of prostanoidreceptors: Properties, distribution, and structure of the receptors andtheir subtypes, Pharmacological Reviews, 45:205-229 (1994)). Whilstthese classes of prostaglandins interact preferably with the designatedmajor classes of receptors (e.g. DP, EP, FP) and subclasses of receptors(e.g. EP₂, EP₃, EP₄), the subscripts associated with the prostaglandindoes not necessarily correspond with the subclass of the receptor(s)with which they interact. Furthermore, it is well known that theseendogenous prostaglandins are non-specific in terms of interacting withthe various classes of prostaglandin receptors. Thus, PGE₂ not onlyinteracts with EP₂ receptors, but can also activate EP₁, EP₂, EP₃ andEP₄ receptors (Coleman et. al., VIII International Union of Pharmacologyclassification of prostanoid receptors: Properties, distribution, andstructure of the receptors and their subtypes, Pharmacological Reviews,45:205-229 (1994)).

In gastric mucosa, various prostaglandins known to be agonists at one ormore of the prostaglandin E receptors have been shown to stimulate mucinsecretion (Waterbury et. al., Stimulation of mucus production andprevention of aspirin induced ulcerogenesis by enprostil in the rat.Proc. West. Pharmacol. Soc., 31:21-3 (1988); Enss et. al., Effects ofPGE ₂ and of different synthetic PGE derivatives on the glycosylation ofpig gastric mucins. Prostaglandins, Leukotrienes, Essent. Fatty Acids,59:49-54 (1998); Guslandi et. al., Gastric effects of a prostaglandinE1-derivative (Rioprostil) on acid, alkaline, and mucus secretion. Clin.Ther., 8:619-23. Katz et. al., Antigastrolesive, gastric antisecretory,diarrheagenic, and mucus-stimulating effects in rats following topicallyapplied rioprostil, a synthetic prostaglandin E1 analog. Life Sci.,41:1591-8 (1987); Waterbury et. al., Stimulatory effect of enprostil, ananti-ulcer prostaglandin, on gastric mucus secretion. Am. J. Med.,81:30-3 (1986); Perkins et. al., Antisecretory, mucosal-protective, anddiarrheagenic activity of a novel synthetic prostaglandin, SC-46275, inthe rat. Drug Dev. Res., 23:349-58 (1991); Bunce et. al., GR63799X—anovel prostanoid with selectivity for EP ₃ receptors. Adv.Prostaglandin. Thromboxane, Leukotriene Res. 21A:379-82 (1990); Sellerset. al., Misoprostol-induced increases in adherent gastric mucusthickness and luminal mucus output. Dig. Dis. Sci., 31:91S-95S (1986);Wilson et. al., Effects of misoprostol on gastric acid and mucussecretion in man. Dig. Dis. Sci., 31:126S-129S (1986)). Of interest inthe present invention are prostaglandins which are believed to exhibitmucin-producing activity by binding to and activating any of the fourrecognized prostaglandin E receptors.

SUMMARY OF THE INVENTION

The present invention is directed to compositions and methods for thetreatment of dry eye and other disorders requiring the wetting of theeye. More specifically, the present invention discloses compositionscontaining prostaglandin E receptor agonists and methods for treatingdry eye type disorders.

Preferred compositions include an effective amount of a prostaglandin Ereceptor agonist for the production of mucins in mammals, and especiallyin humans. The compositions are administered topically to the eye forthe treatment of dry eye.

DETAILED DESCRIPTION OF THE INVENTION

It has now been discovered that certain prostaglandin E receptoragonists stimulate mucin production in human conjuctival epithelium andare therefore believed to be useful in treating dry eye. As used herein,the term “prostaglandin E receptor agonist” refers to any compound whichacts as an agonist or partial agonist at one of the prostaglandin EPreceptors (EP₁, EP₂, EP₃, or EP₄), thereby stimulating mucin productionand/or secretion in the conjunctival epithelium and goblet cellsfollowing topical ocular application. Specifically included in suchdefinition are compounds of the following formula I:

wherein:

R¹=(CH₂)_(n)CO₂R, (CH₂)_(n)CONR⁴R⁵, (CH₂)_(n)CH₂OR⁶, (CH₂)_(n)CH₂NR⁷R⁸,where:

R=H or pharmaceutically acceptable cationic salt moiety, or CO₂R forms apharmaceutically acceptable ester moiety;

R⁴, R⁵=same or different=H, alkyl, or SO₂CH₃, with the proviso that ifone of

R⁴, R⁵=SO₂CH_(3,) then the other=H or alkyl;

R⁶=H, acyl, or alkyl;

R⁷, R⁸=same or different=H, acyl, or alkyl; with the proviso that if oneof

R⁷, R⁸=acyl, then the other=H or alkyl;

n=0 or 2;

----=single or double bond, which can be cumulated (i.e., carbons 4-6can form an allene);

R^(9b)=Cl, and R^(9a)=H, or R^(9b)R^(9a) taken together=O as a carbonyl;

Y=CH₂, O, or

 where

R¹¹=H, alkyl, or acyl;

A=O and B=CH₂; or, A—B=CH₂CH₂ or cis-CH═CH; with the proviso that A≠Owhen Y=O.

one of C, D=H, and the other=CH₃ or OR², where R²=H, acyl, or alkyl; orC=D=H;

E and F=same or different=H or CH₃; or one of E, F=CH₃ and theother=OR², where R² is defined as above; with the proviso that exactlyone of C, D, E, and F=OR²;

X=O or direct bond;

R²⁰=C₂₋₈ alkyl, C₂₋₈ alkenyl, aryl, heteroaryl, aryloxy, orheteroaryloxy, optionally substituted with halo, trihalomethyl, OR³,NR³R²¹, wherein R³=H, alkyl, or acyl; and R²¹=H, alkyl, or acyl; withthe proviso that if one of R³ and R²¹=acyl, then the other=H or alkyl:and wherein the C₂₋₈ alkyl and C₂₋₈ alkenyl may be optionally terminatedby C₃₋₈ cycloalkyl, C₄₋₈ cycloalkenyl, aryl, heteroaryl, aryloxy, orheteroaryloxy, optionally substituted as described above; with theproviso that R²⁰≠aryloxy or heteroaryloxy when X=O;

with the proviso that the following compounds of formula I be excluded:

those wherein all of the following limitations are satisfied:

----=a single bond between carbons 4 and 5 and a single or double bondbetween carbons 5 and 6;

R^(9a)R^(9b)=O as a carbonyl;

Y=CH₂ or

 where

R¹¹ as defined above;

A—B=CH₂CH₂ or CH═CH;

one of C, D=H and the other=OR², where R² is as defined above; and

E and F=same or different=H or CH₃.

Included within the scope of the present invention are the individualenantiomers of the title compounds, as well as their racemic andnon-racemic mixtures. The individual enantiomers can beenantioselectively synthesized from the appropriate enantiomericallypure or enriched starting material by means such as those describedbelow. Alternatively, they may be enantioselectively synthesized fromracemic/non-racemic or achiral starting materials. (AsymmetricSynthesis; J. D. Morrison and J. W. Scott, Eds.; Academic PressPublishers: New York, 1983-1985, volumes 1-5; Principles of AsymmetricSynthesis; R. E. Gawley and J. Aube, Eds.; Elsevier Publishers:Amsterdam, 1996). They may also be isolated from racemic and non-racemicmixtures by a number of known methods, e.g. by purification of a sampleby chiral HPLC (A Practical Guide to Chiral Separations by HPLC; G.Subramanian, Ed.; VCH Publishers: New York, 1994; Chiral Separations byHPLC; A. M. Krstulovic, Ed.; Ellis Horwood Ltd. Publishers, 1989), or byenantioselective hydrolysis of a carboxylic acid ester sample by anenzyme (Ohno, M.; Otsuka, M. Organic Reactions. volume 37, page 1(1989)). Those skilled in the art will appreciate that racemic andnon-racemic mixtures may be obtained by several means, including withoutlimitation, nonenantioselective synthesis, partial resolution, or evenmixing samples having different enantiomeric ratios. Departures may bemade from such details within the scope of the accompanying claimswithout departing from the principles of the invention and withoutsacrificing its advantages. Also included within the scope of thepresent invention are the individual isomers of the disclosed compoundssubstantially free of their respective enantiomers.

As used herein, the terms “pharmaceutically acceptableester”/“pharmaceutically acceptable cationic salt” means anyester/cationic salt that would be suitable for therapeuticadministration to a patient by any conventional means withoutsignificant deleterious health consequences; and “ophthalmicallyacceptable ester”/“ophthalmically acceptable cationic salt” means anypharmaceutically acceptable ester/cationic salt that would be suitablefor ophthalmic application, i.e. non-toxic and non-irritating. Wavy lineattachments indicate that the configuration may be either alpha (α) orbeta (β). The carbon numbering is as indicated in formula I, even whenn=2. Dashed lines on bonds [e.g., between carbons 4 (C-4) and 5 (C-5)]indicate a single or double bond. Two solid lines present specify theconfiguration of the relevant double bond. Hatched lines indicate the αconfiguration. A solid triangular line indicates the β configuration

The term “acyl” represents a group that is linked by a carbon atom thathas a double bond to an oxygen atom and single bond to another carbonatom.

The term “acylamino ” represents a group that is linked by an amino atomthat is connected to a carbon atom has a double bond to an oxygen groupand a single bond to a carbon atom or hydrogen atom.

The term “acyloxy” represents a group that is linked by an oxygen atomthat is connected to a carbon that has a double bond to an oxygen atomand single bond to another carbon atom.

The term “alkenyl” includes straight or branched chain hydrocarbongroups having 1 to 15 carbon atoms with at least one carbon-carbondouble bond. The chain hydrogens may be substituted with other groups,such as halogen. Preferred straight or branched alkeny groups include,allyl, 1-butenyl, 1-methyl-2-propenyl and 4-pentenyl.

The term “alkoxy” represents an alkyl group attached through an oxygenlinkage.

The term “alkyl” includes straight or branched chain aliphatichydrocarbon groups that are saturated and have 1 to 15 carbon atoms. Thealkyl groups may be substituted with other groups, such as halogen,hydroxyl or alkoxy. Preferred straight or branched alkyl groups includemethyl, ethyl, propyl, isopropyl, butyl and t-butyl.

The term “alkylamino” represents an alkyl group attached through anitrogen linkage.

The term “alkynyl” includes straight or branched chain hydrocarbongroups having 1 to 15 carbon atoms with at least one carbon-carbontriple bond. The chain hydrogens may be substituted with other groups,such as halogen. Preferred straight or branched alkynyl groups include,2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl and 2-pentynyl.

The term “aryl” refers to carbon-based rings which are aromatic. Therings may be isolated, such as phenyl, or fused, such as naphthyl. Thering hydrogens may be substituted with other groups, such as loweralkyl, or halogen.

The term “carbonyl” represents a group that has a carbon atom that has adouble bond to an oxygen atom.

The term “carbonylalkoxy” represents a group that is linked by a carbonatom that has a double bond to an oxygen atom and a single bond to analkoxy group.

The term “carbonyloxyl” represents a group that is linked by a carbonatom that has a double bond to an oxygen atom and a single bond to asecond oxygen atom.

The term “cycloalkyl” includes straight or branched chain, saturated orunsaturated aliphatic hydrocarbon groups which connect to form one ormore rings, which can be fused or isolated. The rings may be substitutedwith other groups, such as halogen, hydroxyl or lower alkyl. Preferredcycloalkyl groups include cyclopropyl, cyclobutyl, cylopentyl andcyclohexyl.

The term “dialkylamino” represents two alkyl groups attached through anitrogen linkage.

The term “halogen” and “halo” represents fluoro, chloro, bromo, or iodo.

The term “heteroaryl” refers to aromatic hydrocarbon rings which containat least one heteroatom such as O, S, or N in the ring. Heteroaryl ringsmay be isolated, with 5 to 6 ring atoms, or fused, with 8 to 10 atoms.The heteroaryl ring(s) hydrogens or heteroatoms with open valency may besubstituted with other groups, such as lower alkyl or halogen. Examplesof heteroaryl groups include imidazole, pyridine, indole, quinoline,furan, thiophene, pyrrole, tetrahydroquinoline, dihydrobenzofuran, anddihydrobenzindole.

The term “lower alkyl” represents alkyl groups containing one to sixcarbons (C₁-C₆).

Preferred for purposes of the present invention are those compounds offormula I wherein:

R¹=(CH₂)_(n)CO₂R or (CH₂)_(n)CH₂OH, where R=H, ophthalmically acceptablecationic salt moiety, or lower alkyl; and n=0;

----=single or double bond, which can be cumulated (i.e., carbons 4-6can form an allene);

R^(9b)=Cl, and R^(9a)=H; or R^(9b)R^(9a) taken together=O as a carbonyl;

 where

R¹¹=H;

A—B=cis-CH═CH;

C=D=H;

one of E, F=CH₃ and the other=OR²;

R²=H;

X=direct bond; and

R²⁰=C₂₋₅ alkyl or C₂₋₅ alkenyl, where either is optionally terminated byC₅₋₆ cycloalkyl or C₅₋₆ cycloalkenyl.

Also preferred for purposes of the present invention are those compoundsof formula I, wherein:

R¹=(CH₂)_(n)CO₂R or (CH₂)_(n)CH₂OH, where R=H, ophthalmically acceptablecationic salt moiety, or lower alkyl; and n=0;

----=single or double bond, which can be cumulated (i.e., carbons 4-6can form an allene);

R^(9b)=Cl, and R^(9a)=H;

 where

R¹¹=H;

A—B=cis-CH═CH;

one of C=D=H, and the other=OH;

E=F=CH₃;

X=direct bond; and

R²⁰=C₂₋₅ alkyl or C₂₋₅ alkenyl, where either is optionally terminated byC₅₋₆ cycloalkyl or C₅₋₆ cycloalkenyl.

Also preferred for purposes of the present invention are those compoundsof formula I, wherein:

R¹=(CH₂)_(n)CO₂R or (CH₂)_(n)CH₂OH, where R=H, ophthalmically acceptablecationic salt moiety, or lower alkyl; and n=0;

-----=a double bond between carbons 4 and 5 and a single or double bondbetween carbons 5 and 6;

R^(9a)R^(9b) taken together=O as a carbonyl;

 where

R¹¹=H

A—B=cis-CH═CH;

one of C=D=H, and the other=OH;

E=F=H;

X=O;

R²⁰=phenyl, optionally substituted with Cl or CF₃.

Most preferred of the foregoing compounds are the following:

Compound Name Compound Structure Source Reference* enprostil

Cooper et al., J. Org. Chem., 58:4280-4286 (1993); Park et. al., U.S.Pat. No. 5,571,936. rioprostil

Shriver et al., EP 66475 A2; Kluender et. al., U.S. Pat. No. 4,132,738SC-46275

Kalish et. al., Synth. Commun., 20:1641-5 (1990); Collins et. al., J.Med. Chem., 33:2784-93 (1990); Babiak et. al., U.S. Pat. No. 5,055,604.enisoprost

Babiak et. al., U.S. Pat. No. 5,055,604; Dygos et. al., J. Org. Chem.,56:2549- 52 (1990). nocloprost

Skuballa et. al., U.S. Pat. No, 4,444,788. misoprostol

Commercially available from Cayman Chemical Co., Ann Arbor, MI *To theextent the cited references disclose methods of synthesis for theidentified compounds, those references are hereby incorporated herein.

The prostaglandin E agonists of the present invention may be containedin various types of pharmaceutical compositions, in accordance withformulation techniques known to those skilled in the art. In general,these compounds will be formulated in solutions for topical ophthalmicadministration. Solutions, suspensions and other dosage forms areparticularly preferred for the treatment of dry eye.

The ophthalmic compositions of the present invention will include one ormore compounds of the present invention in a pharmaceutically acceptablevehicle. Various types of vehicles may be used. Aqueous solutions aregenerally preferred, based on ease of formulation, biologicalcompatibility, as well as a patient's ability to easily administer suchcompositions by means of instilling one to two drops of the solutions inthe affected eyes. However, the compounds of the present invention mayalso be readily incorporated into other types of compositions, such assuspensions, viscous or semi-viscous gels, or other types of solid orsemi-solid compositions. Suspensions may be preferred for thosecompounds of the present invention which are less soluble in water. Theophthalmic compositions of the present invention may also includevarious other ingredients, such as buffers, preservatives, co-solventsand viscosity building agents.

An appropriate buffer system (e.g., sodium phosphate, sodium acetate orsodium borate) may be added to prevent pH drift under storageconditions.

Antioxidants may be added to compositions of the present invention toprotect the EP₄ agonists from oxidation during storage. Examples of suchantioxidants include vitamin E and analogs thereof, ascorbic acid andbutylated hydroxytoluene (BHT).

Ophthalmic products are typically packaged in multidose form.Preservatives are thus required to prevent microbial contaminationduring use. Suitable preservatives include: benzalkonium chloride,thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethylalcohol, edetate disodium, sorbic acid, polyquaternium-1, or otheragents known to those skilled in the art. Such preservatives aretypically employed at a level of from 0.001 to 1.0% weight/volume (“%w/v”).

In general, the doses used for the above described purposes will vary,but will be in an effective amount to increase mucin production in theeye and thus eliminate or improve dry eye conditions. As used herein,the term “pharmaceutically effective amount” refers to an amount whichimproves the dry eye condition in a human patient. When the compositionsare dosed topically, they will generally be in a concentration range offrom 0.001 to about 1.0% w/v, with 1-2 drops administered 1-4 times perday.

As used herein, the term “pharmaceutically acceptable carrier” refers toany vehicle which, when formulated, is safe, and provides theappropriate delivery for the desired route of administration of aneffective amount of at least one prostaglandin E agonist of the presentinvention.

The invention has been described by reference to certain preferredembodiments; however, it should be understood that it may be embodied inother specific forms or variations thereof without departing from itsspirit or essential characteristics. The embodiments described above aretherefore considered to be illustrative in all respects and notrestrictive, the scope of the invention being indicated by the appendedclaims rather than by the foregoing description.

What is claimed is:
 1. A method for the treatment of dry eye in mammalscomprising administering to an affected eye, a pharmaceuticallyeffective amount of a compound of formula I:

wherein: R¹=(CH₂)_(n)CO₂R, (CH₂)_(n)CONR⁴R⁵, (CH₂)_(n)CH₂OR⁶,(CH₂)_(n)CH₂NR⁷R⁸, where: R=H or pharmaceutically acceptable cationicsalt moiety, or CO₂R forms a pharmaceutically acceptable ester moiety;R⁴, R⁵=same or different=H, alkyl, or SO₂CH₃, with the proviso that ifone of R⁴, R⁵=SO₂CH₃, then the other=H or alkyl; R⁶=H, acyl, or alkyl;R⁷, R⁸=same or different=H, acyl, or alkyl; with the proviso that if oneof R⁷, R⁸=acyl, then the other=H or alkyl; n=0 or 2; ----=single ordouble bond, which may be cumulated to form an allene; R^(9b)=Cl, andR^(9a)=H, or R^(9b)R^(9a) taken together=O as a carbonyl; Y=CH₂, O, or

 where R¹¹=H, alkyl, or acyl; A=O and B=CH₂; or, A—B=CH₂CH₂ orcis-CH═CH; with the proviso that A≠O when Y=O. one of C, D=H, and theother=CH₃ or OR², where R²=H, acyl, or alkyl; or C=D=H; E and F=same ordifferent=H or CH₃; or one of E, F=CH₃ and the other=OR², where R² isdefined as above; with the proviso that exactly one of C, D, E, andF=OR²; X=O or direct bond; R²⁰=C₂₋₈ alkyl, C₂₋₈ alkenyl, aryl,heteroaryl, aryloxy, or heteroaryloxy, optionally substituted with halo,trihalomethyl, OR³, NR³R²¹, wherein R³=H, alkyl, or acyl; and R²¹=H,alkyl, or acyl; with the proviso that if one of R³ and R²¹=acyl, thenthe other=H or alkyl; and wherein the C₂₋₈ alkyl and C₂₋₈ alkenyl may beoptionally terminated by C₃₋₈ cycloalkyl, C₄₋₈ cycloalkenyl, aryl,heteroaryl, aryloxy, or heteroaryloxy, optionally substituted asdescribed above; with the proviso that R²⁰≠aryloxy or heteroaryloxy whenX=O; with the proviso that the following compounds of formula I beexcluded: those wherein all of the following limitations are satisfied:----=a single bond between carbons 4 and 5 and a single or double bondbetween carbons 5 and 6; R^(9a)R^(9b)=O as a carbonyl; Y=CH₂ or

 where R¹¹ as defined above; A—B=CH₂CH₂ or CH═CH; one of C, D=H and theother=OR², where R² is as defined above; and E and F=same or different=Hor CH₃.
 2. The method of claim 1, wherein the mammal is a human and thecompound is administered topically.
 3. The method of claim 2, whereinfor the compound of formula I: R¹=(CH₂)_(n)CO₂R or (CH₂)_(n)CH₂OH, whereR=H, ophthalmically acceptable cationic salt moiety, or lower alkyl; andn=0; -----=single or double bond, which may be cumulated to form anallene; R^(9b)=Cl, and R^(9a)=H; or R^(9b)R^(9a) taken together=O as acarbonyl;

 where R¹¹=H; A—B=cis-CH═CH; C=D=H; one of E, F=CH₃ and the other=OR²,where R²=H; X=direct bond; and R²⁰=C₂₋₅ alkyl or C₂₋₅ alkenyl, whereeither is optionally terminated by C₅₋₆ cycloalkyl or C₅₋₆ cycloalkenyl.4. The method of claim 3, wherein the compound is selected from thegroup consisting of: rioprostil, SC 46275, enisoprost, and misoprostol.5. The method of claim 2, wherein for the compound of formula I:R¹=(CH₂)_(n)CO₂R or (CH₂)_(n)CH₂OH, where R=H, ophthalmically acceptablecationic salt moiety, or lower alkyl; and n=0; ----=single or doublebond, which may be cumulated to form an allene; R^(9b)=Cl, and R^(9a)=H;

 where R¹¹=H; A—B=cis-CH═CH; one of C=D=H, and the other=OH; E=F=CH₃;X=direct bond; and R²⁰=C₂₋₅ alkyl or C₂₋₅ alkenyl, where either isoptionally terminated by C₅₋₆ cycloalkyl or C₅₋₆ cycloalkenyl.
 6. Themethod of claim 5, wherein the compound is nocloprost.
 7. The method ofclaim 2, wherein for the compound of formula I: R¹=(CH₂)_(n)CO₂R or(CH₂)_(n)CH₂OH, where R=H, ophthalmically acceptable cationic saltmoiety, or lower alkyl; and n=0; ----=a double bond between carbons 4and 5 and a single or double bond between carbons 5 and 6; R^(9a)R^(9b)taken together=O as a carbonyl;

 where R¹¹=H; A—B=cis-CH═CH; one of C=D=H, and the other=OH; E=F=H; X=O;R²⁰=phenyl, optionally substituted with Cl or CF₃.
 8. The method ofclaim 7, wherein the compound is enprostil.